Building the route to metastasis

Infection triggers the release of the phospholipid S1P, which stimulates macrophages to launch a proinflammatory response, including secretion of the protein lipocalin 2 (LCN2). Dying tumor cells also release S1P. Using human primary cells and mouse models, Jung et al. discovered that a multicellular signaling circuit involving the release of S1P from dying breast tumor cells to stimulate release of LCN2 from tumor-associated macrophages stimulated the release of the lymphangiogenic factor VEGFC from lymphatic endothelial cells, thus promoting the growth of lymphatic vessels in the tumor microenvironment. Inhibiting the pathway suppressed lymphangiogenesis and metastasis in mice. The findings reveal not only therapeutic targets but also a way that therapy-induced tumor cell death and viral or bacterial infection could prime the microenvironment for metastasis (see also the Focus by Rodvold and Zanetti).